ABSTRACT Investigation to Minimize Prolapse Recurrence Of the Vagina using Estrogen (IMPROVE) Pelvic organ prolapse, a condition in which the pelvic organs (bladder, vagina, cervix and uterus) herniate through the vaginal opening, is a very common pelvic floor disorder with substantial social and psychological implications that affect the quality of life for women. Increasing age is a known risk factor for prolapse and urinary incontinence. The lifetime risk of surgery for prolapse or stress urinary incontinence is 20% (and 13% for prolapse surgery alone); projections for 2050 are that the number of US women with prolapse will increase 46% from 3.3 to 4.9 million, placing an even greater burden on our healthcare system. Recurrent prolapse and reoperation are also common; at least 17% of patients who have surgical repairs undergo repeat operations within 10 years, and a greater number have recurrence of bothersome symptoms. To address these high failure and reoperation rates?particularly in aging or post-menopausal women?there is an urgent need to identify adjuncts to native tissue prolapse repairs that may prevent or minimize recurrent disease. Our pilot trial of preoperative intravaginal estrogen treatment vs. placebo in postmenopausal women with prolapse demonstrated increased thickness and greater content of well-organized collagen (i.e., type I) of the vaginal wall muscularis in estrogen-treated women. Up-regulation of collagen type I was accompanied by down- regulation of several proteases, suggesting perioperative vaginal estrogen in postmenopausal women with prolapse may mitigate surgical induction of several degradative enzymes and thereby improve long-term maintenance of connective tissue integrity of the pelvic floor. In this application, we propose a double-blind randomized trial of intravaginal estrogen (conjugated estrogens, 0.625mg/1g cream) vs. placebo in postmenopausal women (n=276 total) with symptomatic prolapse beyond the hymen planning transvaginal native tissue repairs. Medication will be continued 1 year postoperatively, i.e. until scar remodeling is complete. We aim to determine if pre- and postoperative intravaginal estrogen therapy (i) results in anatomic and patient-reported subjective improvement in pelvic organ support, and (ii) impacts other pelvic floor disorders (overactive bladder and incontinence, sexual function and pain, postoperative cystitis), satisfaction, quality of life, and vaginal wound healing. Finally, (iii) we will determine the potential mechanisms by which local estrogen treatment alters pelvic organ support by examining full-thickness vaginal wall biopsies taken at the time of surgery for histologic, connective tissue, and smooth muscle synthesis and degradative changes. We expect this will highlight other novel targets for future therapies in prolapse repair and prevention.